Biomedical subjects
Publications and source records attributed to C J Fowler.
The activity of platelet monoamine oxidase in Down's syndrome cases was significantly lower than that of controls. This difference was found for both males and females, and with tyramine, tryptamine and beta-phenethylamine as substrate. The Km values of the monoamine oxidase towards tryptamine as substrate from controls and Down's syndrome patients were similar.
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The monoamine oxidase B (MAO-B) selective inhibitor J-508 (N-methyl-N-propargyl-(1-indanyl)-ammonium chloride) appears to interact with MAO-B in a manner consistent with a "suicide" reaction. Because of this property, J-508 could be used, under the appropriate conditions, to "titrate" the concentration of MAO-B active centres in the human platelet, although some non-specific binding of this compound to sites other than the active centre of this enzyme form was found, thus limiting the accuracy of the titration method. The molecular characteristics of human platelet MAO-B (Km, Vmax, approximate enzyme concentrations and molecular turnover members) towards three of its monoamine substrates have been estimated. The natural variation of platelet MAO-B activity from individual to individual is due to a variation in the Vmax without a variation in the Km towards benzylamine is substrate, and is based, at least in part, upon a variation in the concentration of this enzyme form.
The interaction of clorgyline and L-deprenil with the -A and -B forms of human brain monoamine oxidase (MAO) has been studied. Both compounds inhibit cerebrocortical MAO in a manner consistent with a 'suicide' inactivation of the enzyme. The interaction of clorgyline with the -A form of the enzyme appears to take place almost entirely at specific binding sites, and the conditions required for this inhibitor to 'titrate' the concentrations of MAO-A have been elucidated. L-Deprenil has also been used to titrate the concentration of the -B form of MAO in cerebrocortical homogenates, but there is a considerable degree of non-specific binding of this compound. The two inhibitors have been used to titrate the concentrations of the two enzyme forms in frontal cortex homogenates from different age groups. There was a significantly higher MAO-B activity for the age range 73--95 years than for the age range 2--63 years. No significant differences between the two age groups were found for MAO-A. The activity of MAO-A in the samples correlated very well with the concentration of this enzyme form. Titration of the B-form of the enzyme with L-deprenil indicated an increased enzyme concentration with age, although other factors, such as the non-specific binding of this compound, could contribute to this effect.
The interaction of the substrate-selective irreversible inhibitor J-508 [N-methyl-N-propargyl-(1-indanyl)-ammonium hydrochloride] with the B form of human brain monoamine oxidase has been investigated, and the conditions necessary for this inhibitor to "titrate" the concentration of this enzyme form determined. It was found that the concentration of monoamine oxidase-B determined in this way was the same when either benzylamine or beta-phenethylamine was used to assay for activity, which would indicate that this enzyme form is not heterogeneous. Furthermore, the variation in activity from sample to sample was found to be due to a variation in the concentration of available monoamine oxidase-B active centers, raher than due to a variation in the molecular turnover numbers of this enzyme form towards its amine substrates.
The effect of age upon monoamine oxidase -A and -B (MAO-A and -B) in 23 different, regions of human brain was determined. There was a significant positive correlation with age in 19 out of 23 regions for MAO-B, but no positive correlation with age was found for MAO-A. The increased MAO-B activity was found, in 5 out of 5 regions tested, to be due entirely to an increased enzyme concentration, rather than due to an increased molecular turnover number of the enzyme. The responses of the mitochondrial marker enzymes succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) were studied in 5 brain regions, and no consistent change in activity found with age. The lysosomal enzyme acid phosphatase was found to tend towards an increased activity with age. No difference in either the specific activities or molecular characteristics of MAO were found between men and women. Cross-correlation studies of the data, after compensation for the effects of age, indicated that the activities of the two enzyme forms are under some form of organized control across the whole brain. Such a finding is consistent with a genetic regulation of the enzyme forms.
Personality traits, as assessed by personality inventories, and platelet monoamine oxidase activities have been compared in the following two groups of normal subjects: (1) subjects who either have mountaineering as an active hobby or an interest in mountaineering and (2) subjects not interested in mountaineering. The group of subjects interested in mountaineering were found to be sensation seekers, as assessed by the Zuckerman Sensation Seeking Scale, and to have significantly lower platelet monoamine oxidase activities.
The extraction of lipids from rat liver mitochondrial membranes by 2-butanone treatment inhibited the activity of membrane-bound monoamine oxidase -A but not -B. For the -B form, the apparent Michaelis constants of the enzyme towards oxygen and the maximum molecular turnover numbers obtained when beta-phenethylamine and benzylamine were used as substrates were not significantly changed by the lipid-depletion procedure, but the values of the Michaelis constant towards benzylamine was significantly increased after lipid-depletion. The differential sensitivity of beta-phenethylamine and benzylamine oxidation to inhibition by Tris-HCl was not changed after lipid-depletion. The results are consistent with the hypothesis that the mitochondrial membrane lipids, while essential for the activity of the -A form of the enzyme in rat liver, play a more subtle modulatory role in the activity of the -B form.
Pretreatment of rat liver homogenates with 1.5 x 10(-4) M SKF 525A is without effect on the activity of monoamine oxidase-A, but results in a decrease in the concentration of clorgyline required for the inhibition of this enzyme form. Such a result is consistent with the hypothesis that rat liver homogenates contain an SKF 525A-sensitive clorgyline-metabolising system.
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Three experiments are reported. In the first, monetary incentives improved the learning of nonsense words in response to colours only when the test order was the same as presentation order. In the second, incentives increased the recall of spatial location which served as an additional retrieval cue for nonsense words. In the third, noise was used to manipulate arousal. Noise during learning produced a significant decline in recall of locations for nonsense words. The results suggest that incentives increase attentional capacity, while noise does not. Previous results showing that noise increases the use of order cues are discussed and it is suggested that noise induces a type of learning which depends on order cues. Existing hypotheses about the nature of this process are noted but it is argued that further work is needed to select between them.
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The interaction between rat brain monoamine oxidase-B and J-508, an analogue of L-deprenil, has been investigated. J-508 inhibits rat brain monoamine oxidase-B in a manner consistent with a 'suicide' reaction, and is so potent an inhibitor that it produces inhibition at concentrations of the same order as those of the enzyme. This property has been used to determine the nature of the changed monoamine oxidase-B activity in the corpus striatum after hemitransection of rat brain.